The Stress-Induced Cytokine Interleukin-6 Decreases the Inhibition/Excitation Ratio in the Rat Temporal Cortex via Trans-Signaling

• Published in: Biological psychiatry (1969) Vol. 71; no. 7; pp. 574 - 582
• Main Authors: Garcia-Oscos, Francisco, Salgado, Humberto, Hall, Shawn, Thomas, Feba, Farmer, George E., Bermeo, Jorge, Galindo, Luis Charles, Ramirez, Ruben D., D'Mello, Santosh, Rose-John, Stefan, Atzori, Marco
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.04.2012; Elsevier
• Subjects: 2-Br-hexadecanoic acid; Androstadienes - pharmacology; Animals; Biological and medical sciences; Brefeldin A; Brefeldin A - pharmacology; Cytokine Receptor gp130 - antagonists & inhibitors; Disease Models, Animal; Drug Interactions; dynamin inhibitory peptide; Electric Stimulation - methods; Excitatory Postsynaptic Potentials - drug effects; Excitatory Postsynaptic Potentials - physiology; foot-shock; gp130; Inhibitory Postsynaptic Potentials - drug effects; Inhibitory Postsynaptic Potentials - physiology; interleukin-6 (IL-6); Interleukin-6 - antagonists & inhibitors; Interleukin-6 - pharmacology; Interleukin-6 - physiology; lipopolysaccharide (LPS); Lipopolysaccharides; Medical sciences; Muscimol - pharmacology; Oligopeptides - pharmacology; Palmitates - pharmacology; patch-clamp; PI3K/AKT; postsynaptic; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; rat; Rats; stress; Stress, Psychological - chemically induced; Stress, Psychological - physiopathology; temporal cortex; Temporal Lobe - drug effects; Temporal Lobe - physiopathology; trans-signaling; wortmannin; γ-aminobutyric acid (GABA); wortmannin; lipopolysaccharide (LPS); stress; rat; patch-clamp; Brefeldin A; 2-Br-hexadecanoic acid; postsynaptic; dynamin inhibitory peptide; interleukin-6 (IL-6); PI3K/AKT; foot-shock; γ-aminobutyric acid (GABA); gp130; trans-signaling; temporal cortex; Shock; Rat; Central nervous system; Electrophysiology; Patch clamp method; Encephalon; Interleukin 6; Signal transduction; Lipopolysaccharide; P13K/AKT; Inhibition; Rodentia; Cytokine; Temporal cortex; Stress; Foot; Vertebrata; Mammalia; Animal; Neurotransmitter; GABA
• ISSN: 0006-3223; 1873-2402; 1873-2402
• DOI: 10.1016/j.biopsych.2011.11.018

Although it is known that stress elevates the levels of pro-inflammatory cytokines and promotes hyper-excitable central conditions, a causal relationship between these two factors has not yet been identified. Recent studies suggest that increases in interleukin 6 (IL-6) levels are specifically associated with stress. We hypothesized that IL-6 acutely and directly induces cortical hyper-excitability by altering the balance between synaptic excitation and inhibition. We used patch-clamp to determine the effects of exogenous or endogenous IL-6 on electrically evoked postsynaptic currents on a cortical rat slice preparation. We used control subjects or animals systemically injected with lipopolysaccharide or subjected to electrical foot-shock as rat models of stress. In control animals, IL-6 did not affect excitatory postsynaptic currents but selectively and reversibly reduced the amplitude of inhibitory postsynaptic currents with a postsynaptic effect. The IL-6-induced inhibitory postsynaptic currents decrease was inhibited by drugs interfering with receptor trafficking and/or internalization, including wortmannin, Brefeldin A, 2-Br-hexadecanoic acid, or dynamin peptide inhibitor. In both animal models, stress-induced decrease in synaptic inhibition/excitation ratio was prevented by prior intra-ventricular injection of an analog of the endogenous IL-6 trans-signaling blocker gp130. Our results suggest that stress-induced IL-6 shifts the balance between synaptic inhibition and excitation in favor of the latter, possibly by decreasing the density of functional γ-aminobutyric acid A receptors, accelerating their removal and/or decreasing their insertion rate from/to the plasma membrane. We speculate that this mechanism could contribute to stress-induced detrimental long-term increases in central excitability present in a variety of neurological and psychiatric conditions.